Joyce O’Shaughnessy, MD: We hear a lot about homologous recombination deficiency (HRD) and hopes for being able to find other patients, who may not be a germline BRCA carrier, in whom we may eventually be able to offer PARP inhibitors to. Where do we stand, right now, in trying to identify these patients with some sort of other surrogate diagnostic besides BRCA testing?

Nadine Tung, MD: I think that’s the goal—to find breast cancers in the non–germline BRCA carriers and to determine who will respond to PARP inhibitors and other DNA damage agents. I think they’re being developed. I would start by saying they’re not in clinical use yet. I would categorize them. I would say that one group looks at genomic loss, and I would say that’s like the Myriad HRD assay that many of us have read or heard about. That was tested in the TNT trial, to see whether you could identify those patients with breast cancer who would also benefit more from platinum and docetaxel. It was not successful. There was a criticism regarding the fact that they used primary breast cancers and did not do a biopsy in the metastatic setting. But that didn’t pan out.

On the other hand, in the neoadjuvant setting, there are some reports that state that a higher HRD score will predict for response to platinum or some other chemotherapy. So there may be something there. A whole other approach (rather than genomic loss) looks at these mutational signatures. The concept is, in BRCA-associated breast cancer, there are signatures. There are combinations. There are patterns of mutations in the tumor, and there are several that are characteristic of those tumors. So can you look for those mutational signatures in other breast cancers? That may predict for similar response to treatment. We have assays, or tools, like HRDetect, that use whole genome sequencing. Again, in the reports, things look very sensitive for being able to identify patients with germline or somatic BRCA mutations or silencing of the BRCA genes. But again, I think we need to wait and see whether these are going to pan out in the clinic.

Joyce O’Shaughnessy, MD: There is a lot going on. There is a lot of interest in understanding the mechanism of DNA repair in these other cancers. Can we exploit that? But there is nothing for us, today, in the clinic. There is nothing for us yet.

Nadine Tung, MD: Correct.

Joyce O’Shaughnessy, MD: Tiffany, where are we going with the PARP inhibitor? We’ve got the single agent. It’s a good start, but what can we add to these things to help make the next advance? What’s the most exciting research that is going on?

Tiffany Traina, MD: There’s a trial that recently reported out in Oncology. Often when we find a drug that works, we try to combine rational combinations with the hope that it will work even better for our patients. Immuno-oncology has been such a hot field, and checkpoint inhibitors have been exciting. A recent presentation by Susan Domchek on the MEDIOLA study looked at partnering olaparib with an anti–PD-L1 inhibitor. This was a single-arm study. There was a lead-in of the single-agent PARP inhibitor. And then investigators added in the anti–PD-L1 antibody. The primary endpoint was a disease control rate in a very short window of about 12 weeks. The study demonstrated about an 80% disease control rate at 12 weeks, which is essentially what they were aiming for. But when you look at something like an objective response rate, it was quite comparable with the olaparib arm in OlympiAD. So in that setting, I’m not quite sure how much benefit there is in adding in an immuno-oncology agent to single-agent olaparib.

But it does raise the idea of that paradigm, perhaps, as a maintenance strategy, which is another area to look into. We’ve talked a lot about platinum sensitivity and the response to platinum as being enriching for folks who are going to respond to PARP inhibitors. The DORA study, which is soon to open and accrue, is trying to answer that very question by using standard-of-care platinum chemotherapy as a predictor, if you will, to determine who will respond to a PARP inhibitor. So that trial looks at olaparib in patients who have responded to a platinum and adds durvalumab to it as a maintenance strategy. The consideration is that this is a tolerable regimen, getting away from the cytotoxicity. But you’ve potentially enriched for patients with wild-type BRCA who may respond to a PARP inhibitor.

Joyce O’Shaughnessy, MD: I guess we’ll see whether the addition of durvalumab might help the progression-free survival. It’s too soon to know. But when you look at the response rates, safety was certainly all right?

Tiffany Traina, MD: Yes, exactly.

Joyce O’Shaughnessy, MD: We don’t have enough data yet, but hopefully they will come. Like you said, even in the wild-type setting, this could be really interesting. Speaking of maintenance and ovarian cancer, it’s tempting.

Nadine Tung, MD: Yes.

Joyce O’Shaughnessy, MD: The BRCA patients will probably be starting with olaparib anyway. But what’s the possibility? Tell us about the ovarian cancer situation?

Nadine Tung, MD: The ovarian cancer treatment world has been ahead of us, in that respect. They use PARP inhibitors as maintenance in patients who have ovarian cancer that has relapsed. It is platinum sensitive. Results from several studies have shown that using a PARP inhibitor as maintenance improves the progression-free survival, when compared with a PARP inhibitor. So they’ve been doing that for a while. Interestingly, I think there are differences. That seems to work not only in patients with germline BRCA mutations in ovarian cancer but also in those with somatic mutations. In the breast cancer world, we’ll see whether somatic BRCA mutations respond the same to PARP inhibitors. We don’t know that yet. There are some ongoing trials. In those who don’t, hopefully the platinum sensitivity will be our biologic selector. In general, I think that there’s less BRCA-ness in wild-type breast cancer versus wild-type ovarian cancer. But it’s an interesting approach.

Joyce O’Shaughnessy, MD: I would like to see some randomized trials along those lines. There will be some first-line BRCA patients, in the metastatic setting, who are pretty ill. We’re probably going to want to give combination chemotherapy with a platinum agent. And then once they get a nice response….

Nadine Tung, MD: Take away the toxic platinum and give them a PARP inhibitor.

Joyce O’Shaughnessy, MD: Switch over. So we’re going to be doing that. Otherwise, we’re going to probably start with olaparib. But then the issue becomes: Can we use the platinum sensitivity, as ovarian cancer doctors have done, as an in vivo biologic readout? That really makes a lot of sense. So really exciting days lie ahead. I’m holding out hope for the immuno-oncology/PARP inhibitor combinations. Biologically, they should work really well. The more DNA damage you can cause, the more you’re going to get an antiviral sting response. The immuno-oncology agent could really help that. So I’m holding out hope for that to be the case.

Transcript Edited for Clarity

SELECTEDLANGUAGE

Transcript:

Joyce O’Shaughnessy, MD: We hear a lot about homologous recombination deficiency (HRD) and hopes for being able to find other patients, who may not be a germline BRCA carrier, in whom we may eventually be able to offer PARP inhibitors to. Where do we stand, right now, in trying to identify these patients with some sort of other surrogate diagnostic besides BRCA testing?

Nadine Tung, MD: I think that’s the goal—to find breast cancers in the non–germline BRCA carriers and to determine who will respond to PARP inhibitors and other DNA damage agents. I think they’re being developed. I would start by saying they’re not in clinical use yet. I would categorize them. I would say that one group looks at genomic loss, and I would say that’s like the Myriad HRD assay that many of us have read or heard about. That was tested in the TNT trial, to see whether you could identify those patients with breast cancer who would also benefit more from platinum and docetaxel. It was not successful. There was a criticism regarding the fact that they used primary breast cancers and did not do a biopsy in the metastatic setting. But that didn’t pan out.

On the other hand, in the neoadjuvant setting, there are some reports that state that a higher HRD score will predict for response to platinum or some other chemotherapy. So there may be something there. A whole other approach (rather than genomic loss) looks at these mutational signatures. The concept is, in BRCA-associated breast cancer, there are signatures. There are combinations. There are patterns of mutations in the tumor, and there are several that are characteristic of those tumors. So can you look for those mutational signatures in other breast cancers? That may predict for similar response to treatment. We have assays, or tools, like HRDetect, that use whole genome sequencing. Again, in the reports, things look very sensitive for being able to identify patients with germline or somatic BRCA mutations or silencing of the BRCA genes. But again, I think we need to wait and see whether these are going to pan out in the clinic.

Joyce O’Shaughnessy, MD: There is a lot going on. There is a lot of interest in understanding the mechanism of DNA repair in these other cancers. Can we exploit that? But there is nothing for us, today, in the clinic. There is nothing for us yet.

Nadine Tung, MD: Correct.

Joyce O’Shaughnessy, MD: Tiffany, where are we going with the PARP inhibitor? We’ve got the single agent. It’s a good start, but what can we add to these things to help make the next advance? What’s the most exciting research that is going on?

Tiffany Traina, MD: There’s a trial that recently reported out in Oncology. Often when we find a drug that works, we try to combine rational combinations with the hope that it will work even better for our patients. Immuno-oncology has been such a hot field, and checkpoint inhibitors have been exciting. A recent presentation by Susan Domchek on the MEDIOLA study looked at partnering olaparib with an anti–PD-L1 inhibitor. This was a single-arm study. There was a lead-in of the single-agent PARP inhibitor. And then investigators added in the anti–PD-L1 antibody. The primary endpoint was a disease control rate in a very short window of about 12 weeks. The study demonstrated about an 80% disease control rate at 12 weeks, which is essentially what they were aiming for. But when you look at something like an objective response rate, it was quite comparable with the olaparib arm in OlympiAD. So in that setting, I’m not quite sure how much benefit there is in adding in an immuno-oncology agent to single-agent olaparib.

But it does raise the idea of that paradigm, perhaps, as a maintenance strategy, which is another area to look into. We’ve talked a lot about platinum sensitivity and the response to platinum as being enriching for folks who are going to respond to PARP inhibitors. The DORA study, which is soon to open and accrue, is trying to answer that very question by using standard-of-care platinum chemotherapy as a predictor, if you will, to determine who will respond to a PARP inhibitor. So that trial looks at olaparib in patients who have responded to a platinum and adds durvalumab to it as a maintenance strategy. The consideration is that this is a tolerable regimen, getting away from the cytotoxicity. But you’ve potentially enriched for patients with wild-type BRCA who may respond to a PARP inhibitor.

Joyce O’Shaughnessy, MD: I guess we’ll see whether the addition of durvalumab might help the progression-free survival. It’s too soon to know. But when you look at the response rates, safety was certainly all right?

Tiffany Traina, MD: Yes, exactly.

Joyce O’Shaughnessy, MD: We don’t have enough data yet, but hopefully they will come. Like you said, even in the wild-type setting, this could be really interesting. Speaking of maintenance and ovarian cancer, it’s tempting.

Nadine Tung, MD: Yes.

Joyce O’Shaughnessy, MD: The BRCA patients will probably be starting with olaparib anyway. But what’s the possibility? Tell us about the ovarian cancer situation?

Nadine Tung, MD: The ovarian cancer treatment world has been ahead of us, in that respect. They use PARP inhibitors as maintenance in patients who have ovarian cancer that has relapsed. It is platinum sensitive. Results from several studies have shown that using a PARP inhibitor as maintenance improves the progression-free survival, when compared with a PARP inhibitor. So they’ve been doing that for a while. Interestingly, I think there are differences. That seems to work not only in patients with germline BRCA mutations in ovarian cancer but also in those with somatic mutations. In the breast cancer world, we’ll see whether somatic BRCA mutations respond the same to PARP inhibitors. We don’t know that yet. There are some ongoing trials. In those who don’t, hopefully the platinum sensitivity will be our biologic selector. In general, I think that there’s less BRCA-ness in wild-type breast cancer versus wild-type ovarian cancer. But it’s an interesting approach.

Joyce O’Shaughnessy, MD: I would like to see some randomized trials along those lines. There will be some first-line BRCA patients, in the metastatic setting, who are pretty ill. We’re probably going to want to give combination chemotherapy with a platinum agent. And then once they get a nice response….

Nadine Tung, MD: Take away the toxic platinum and give them a PARP inhibitor.

Joyce O’Shaughnessy, MD: Switch over. So we’re going to be doing that. Otherwise, we’re going to probably start with olaparib. But then the issue becomes: Can we use the platinum sensitivity, as ovarian cancer doctors have done, as an in vivo biologic readout? That really makes a lot of sense. So really exciting days lie ahead. I’m holding out hope for the immuno-oncology/PARP inhibitor combinations. Biologically, they should work really well. The more DNA damage you can cause, the more you’re going to get an antiviral sting response. The immuno-oncology agent could really help that. So I’m holding out hope for that to be the case.